Chemotherapy is widely used to eliminate cancerous cells. Some chemo-therapeutic agents kill a cell during any phase of the cycle (these are called cell-cycle non-specific), others kill during a specific phase and are unable to work on the resting phase cells (called cell-cycle specific). However, a combination of specific and non-specific chemotherapeutics has been shown as a better chemotherapeutic strategy in certain circumstances. Most chemotherapeutic regimens include at least one drug targeting DNA or an enzyme acting on DNA. Drugs that have been known to target the S phase of the cell cycle, most effectively, include for example, cross-linking agents such as cisplatin and its derivatives and small molecule inhibitors of topoisomerases.
Topoisomerases are a group of enzymes that control the juxtaposed intra molecular stress in DNA due to replication or transcription, by catalyzing the breaking and rejoining of the phosphodiester backbone. Type I topoisomerases change DNA linking number by cutting one strand of a DNA double helix and then rejoining the cut strand. On the other hand, type II topoisomerases relax supercoiled DNA by cutting both strands of DNA double helix, followed by passing DNA strands through it, and then re-annealing the cut strands. Type I topoisomerase makes single-stranded nicks to relieve supercoiling that generates during DNA replication and transcription. Type II topoisomerase act as a molecular motor during the cell cycle, using the energy gained from ATP hydrolysis to introduce tight supercoils into the DNA helix in order to condense the chromosome. Because this process must be highly regulated, type II topoisomerase can form molecular complexes with important cell-cycle regulators (such as p53, TopBP1, 14-3-3 epsilon, and Cdc2) to ensure that chromosome condensation occurs at the correct time in the cell cycle.
Open (relaxed) and closed (condensed) conformations of chromatin occur through acetylation and de-acetylation in eukaryotes. Histone Acetyl Transferase (HAT) mediated acetylation permits chromatin remodeling complexes and transcription factors to access DNA and induce gene expression, respectively. On the contrary, Histone Deacetylases (HDAC) repress gene expression by de-acetylating histone tails which result in chromatin condensation. Earlier studies have shown increased HDAC activity in cancer cells.